The transdermal route of parenteral delivery of drugs provides many advantages over other administrative routes, and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610. The disclosures of the above patents are incorporated herein by reference.
In many instances, drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered at therapeutically effective rates from reasonably sized systems.
In an effort to increase skin permeability, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the drug in the presence of a permeation enhancer. Various materials have been suggested for this purpose, as described in U.S. Pat. Nos. 3,472,931, 3,527,864, 3,896,238, 3,903,256, 3,952,099, 4,046,886, 4,130,643, 4,130,667, 4,299,826, 4,335,115, 4,343,798, 4,379,454, 4,405,616 and 4,746,515, all of which are incorporated herein by reference; British Pat. No. 1,001,949; and Idson, Percutaneous Absorption, J. Pharm. Sci., vol. 64, No. b6, June 1975, pp 901-924 (particularly 919-921).
To be considered useful, a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of drugs. More importantly, it should be able to enhance the skin permeability such that the drug delivery rate from a reasonably sized system (preferably 5-50 cm.sup.2) is at therapeutic levels. Additionally, the enhancer, when applied to the skin surface, should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably, it should be capable of delivering drugs without producing topical reactions, burning or tingling sensations.
The present invention greatly increases oxybutynin permeability through the skin, and also reduces the lag time between application of the oxybutynin to the skin and attainment of the desired therapeutic effect.
While it is known in the art to combine permeation enhancers, this invention utilizes a novel combination of a monoglyceride and a lactate ester. Further, the invention utilizes a specific concentration of each of the novel components. The combined effect and, further, specific concentrations, of the components produce a significant and surprising improvement over use of either a monoglyceride or a lactate ester alone or the combination in nonspecified concentrations.
Neurogenic bladder disease is a disorder involving loss of control of urination. The major symptoms of this disease are urinary frequency, urinary retention or incontinence. There are two types of lesions that cause a neurogenic bladder. The first, upper motoneuron lesion, leads to hypertonia and hyperreflexia of the bladder, a spastic condition, giving rise to symptoms of urinary frequency and incontinence. The second lesion, a lower motoneuron lesion, involves hypotonia and hyporeflexia of the bladder. The major symptoms in this condition are urinary retention, since the voiding reflex has been lost, and incontinence, which occurs when the bladder "leaks", being full to overflowing.
The majority of neurogenic bladder patients have the spastic or hypertonic bladder. The clinician usually attempts to convert the condition of hyperreflexia and hypertonia to hypotonia, thereby treating the primary problem of incontinence. When the condition has been converted to hypotonia, it can be managed by intermittent catheterization. However, there is a significant population of patients who cannot be converted completely from the hypertonic to the hypotonic condition, and who still find they have urinate every hour or are incontinent.
The use of oxybutynin chloride, as approved by the FDA in the United States, is described in the 1992 Physician's Desk Reference, pages 1332 through 1333 with reference to the drug Ditropan.RTM. manufactured by Marion Merrell Dow. Oxybutynin is normally administered to human beings orally at relatively high doses (5 mg tablets taken two to four times a day). Oxybutynin has been incorporated into tablets, capsules, granules or pills containing 1-5 mg, preferably 5 mg, of oxybutynin chloride, syrups containing 1-5 mg, preferably 5 mg, of oxybutynin chloride per 5 mL and transdermal compositions (creams or ointments) containing 1-10 weight percent ("wt %") oxybutynin chloride. See, BE 902605.
In U.S. Pat. No. 4,747,845, oxybutynin was listed as an agent that could be incorporated into a transdermal synthetic resin matrix system for extended duration drug release, but oxybutynin was not used in the device. In U.S. Pat. No. 4,928,680 oxybutynin was given as a pharmacologically active agent suitable for transdermal delivery, but as with the above reference, oxybutynin was not incorporated into the device.
Oxybutynin has been incorporated into a device having a water impermeable barrier layer, a reservoir containing oxybutynin in contact with the inner surface of the barrier layer and a removable protector layer in contact with the other surface of the reservoir. The reservoir was a polyurethane fiber mat impregnated with an aqueous solution containing 25 mg/mL of oxybutynin. The device was placed on a 20 .mu.m thick polybutadiene film. The non-barrier carrying surface was in contact with 0.05 M isotonic phosphate buffer solution. The in vitro release rate measured was approximately 12 mg over 24 hours through a 49 cm.sup.2 area or 10 .mu.g/cm.sup.2.hr. (U.S. Pat. No. 4,784,857 and EP 0 250 125).
In Pharm Res, "Development of Transdermal Delivery Systems of Oxybutynin: In-Vivo Bioavailability", P. Keshary et al, (NY)8 (10 Supp) 1991, p. S205 three types of transdermal delivery systems, using matrix-diffusion controlled and membrane-permeation controlled technologies were discussed. The in vitro permeation rate of about 9, 12 and 12 .mu.g/cm.sup.2.hr and in vitro release rates (sink condition) of about 1160, 402 and 57.2 .mu.g/cm.sup.2.hr were obtained from Silastic monolithic, acrylic pressure sensitive adhesive matrix and reservoir type delivery systems, respectively. In humans, steady state plasma concentrations of about 1.86 ng/mL were obtained after 6 hours of application of a single 20 cm.sup.2 patch of the acrylic pressure sensitive adhesive matrix type.
While it is known in the art to formulate a dual permeation enhancer system, see eg, European patent publication numbers 0295411 and 0368339, this invention utilizes a novel combination of oxybutynin with a monoglyceride and a lactate ester. Further, the invention utilizes novel concentrations of the monoglyceride/lactate ester permeation enhancer combination. The combined effect of these two permeation enhancers and further, the specific concentrations, ie, 15 to 25 wt % of monoglyceride and 8 to 25 wt % of lactic acid ester, produces a significant and surprising improvement, ie, more than an additive effect, over use of either a monoglyceride or a lactate ester alone with oxybutynin or the combination in nonspecified concentrations.